Β-amino Acid Research Articles

Stereocontrolled synthesis of some novel functionalized heterocyclic amino ester and amide derivatives with multiple stereocenters.

The synthesis of some novel functionalized fused-ring β-amino lactones and lactams with multiple chiral centers has been attempted from readily available strained bicyclic β-amino acids via a stereocontrolled synthetic route. The key step was ring-rearrangement metathesis of allyl/propargyl esters or N-allylated/N-propargylated amides of (oxa)norbornene β-amino acids. The RRM transformations [ring-opening metathesis (ROM)/ring-closing metathesis (RCM) or ring-opening metathesis (ROM)/ring-closing enyne metathesis (RCEYM)] have been investigated using some commercially available catalysts. Importantly, the procedure used in this synthetic process does not affect the configurations of the chiral centers. This means that the structure of the starting (oxa)norbornene β-amino acids predetermines the configuration of the formed products.

Lewis acid-catalyzed formal 1,3-aminomethyl migration.

Here we report a Lewis acid-catalyzed 1,3-aminomethyl migration rection. When δ-amino acid derivatives were treated with a catalytic amount of Sc(OTf)3, 1,3-migration of the aminomethyl group proceeded smoothly to afford β-amino acid derivatives in moderate to good chemical yields. Detailed investigation suggested that this migration reaction proceeded through the fragmentation/recombination pathway.

A switch in N-terminal capping of β-peptides creates novel self-assembled nanoparticles.

Small tripeptides composed entirely of β3-amino acids have been shown to self-assemble into fibres following acylation of the N-terminus. Given the use of Fmoc as a strategy to initiate self-assembly in α-peptides, we hypothesized that the acyl cap can be replaced by an Fmoc without perturbation to the self-assembly and enable simpler synthetic protocols. We therefore replaced the N-acyl cap for an Fmoc group and herein we show that these Fmoc-protected β3-peptides produce regular spherical particles, rather than fibrous structures, that are stable and capable of encapsulating cargo. We then demonstrated that these particles were able to deliver cargo to cells without any obvious signs of cytotoxicity. This is the first description of such regular nanoparticles derived from Fmoc-protected β3-peptides.

Biologically potent organotin(iv) complexes of N-acetylated β-amino acids with spectroscopic, X-ray powder diffraction and molecular docking studies.

Twelve novel organotin(iv) complexes (1-12) of N-acetylated β-amino acids (L1-L8) were synthesized and characterized by elemental analysis, FTIR, multinuclear (1H, 13C, 119Sn) NMR, EI-MS and powder XRD techniques. The XRD results determined lattice parameters, average particle size, and intrinsic strain and confirmed the crystalline nature of complexes as face centered cubic phases. Molecular docking analysis using a catalytic pocket of the α-glucosidase enzyme indicated that most of the compounds displayed a well-fitted orientation and occupied important amino acids in the enzyme's catalytic pocket. Furthermore, in vitro α-glucosidase inhibitory activity results revealed that L1 and complexes 4, 6 and 10 showed the highest activity with IC50 values of 21.54 ± 0.45, 37.96 ± 0.81 and 35.20 ± 1.02, respectively, compared to standard acarbose with an IC50 value of 42.51 ± 0.21. In addition, in vivo antidiabetic activity of selected compounds using alloxan induced diabetic rabbits showed that L4 and complexes 4, 6, 10, 12 showed significant activities like standard metformin. Anti-bacterial activity against the selected Gram-positive and Gram-negative bacterial strains has the following order Escherichia coli > Pseudomonas aeruginosa > Staphylococcus aureus > Bacillus subtilis. Similarly, antioxidant activity by the DPPH scavenging method was also studied with following results: triorganotin > diorganotin > ligands.

Conformational landscapes of artificial peptides predicted by various force fields: are we ready to simulate β-amino acids?

With the introduction of artificial peptides as antimicrobial agents and organic catalysts, numerous efforts have been made to design foldamers with desirable structures and functions. Computational tools are a helpful proxy for revealing the dynamic structures at atomic resolution and understanding foldamer's complex structure-function relationships. However, the performance of conventional force fields in predicting the structures of artificial peptides has not been systematically evaluated. In this study, we critically assessed three popular force fields, AMBER ff14SB, CHARMM36m, and OPLS-AA/L, in predicting conformational propensities of a β-peptide foldamer at monomer and hexamer levels. Simulation results were compared to those obtained from quantum chemistry calculations and experimental data. We also utilised replica exchange molecular dynamics simulations to investigate the energy landscape of each force field and assess the similarities and differences between force fields. We compared different solvent systems in the AMBER ff14SB and CHARMM36m frameworks and confirmed the unanimous role of hydrogen bonds in shaping energy landscapes. We anticipate that our data will pave the way for further improvements to force fields and for understanding the role of solvents in peptide folding, crystallisation, and engineering.

Differential membrane binding of α/β-peptide foldamers: implications for cellular delivery and mitochondrial targeting.

The intrinsic pathway of apoptosis is regulated by the Bcl-2 family of proteins. Inhibition of the anti-apoptotic members represents a strategy to induce apoptotic cell death in cancer cells. We have measured the membrane binding properties of a series of peptides, including modified α/β-peptides, designed to exhibit enhanced membrane permeability to allow cell entry and improved access for engagement of Bcl-2 family members. The peptide cargo is based on the pro-apoptotic protein Bim, which interacts with all anti-apoptotic proteins to initiate apoptosis. The α/β-peptides contained cyclic β-amino acid residues designed to increase their stability and membrane-permeability. Dual polarisation interferometry was used to study the binding of each peptide to two different model membrane systems designed to mimic either the plasma membrane or the outer mitochondrial membrane. The impact of each peptide on the model membrane structure was also investigated, and the results demonstrated that the modified peptides had increased affinity for the mitochondrial membrane and significantly altered the structure of the bilayer. The results also showed that the presence of an RRR motif significantly enhanced the ability of the peptides to bind to and insert into the mitochondrial membrane mimic, and provide insights into the role of selective membrane targeting of peptides.

β-Peptides incorporating polyhydroxylated cyclohexane β-amino acid: synthesis and conformational study.

We describe the synthesis of trihydroxylated cyclohexane β-amino acids from (-)-shikimic acid, in their cis and trans configuration, and the incorporation of the trans isomer into a trans-2-aminocyclohexanecarboxylic acid peptide chain. Subsequently, the hydroxyl groups were partially or totally deprotected. The structural study of the new peptides by FTIR, CD, solution NMR and DFT calculations revealed that they all fold into a 14-helix secondary structure, similarly to the homooligomer of trans-2-aminocyclohexanecarboxylic acid. This means that the high degree of substitution of the cyclohexane ring of the new residue is compatible with the adoption of a stable helical secondary structure and opens opportunities for the design of more elaborate peptidic foldamers with oriented polar substituents at selected positions of the cycloalkane residues.

A transaminase with β-activity from Variovorax boronicumulans for the production of enantiopure β-amino acids

Enantioselective transamination of amino acids is a great challenge in biotechnology as suitable enzymes with wide substrate spectrum are rare. Here, we present a new transaminase from Variovorax boronicumulans (VboTA, Variovorax boronicumulansω-transaminase) which is specific for β-amino acids.The amino acid sequence of VboTA is similar to an ω-transaminase from Variovorax paradoxus, for which a crystal-structure is available. This similarity is allowing us to classify VboTA as a fold type 1 ω-transaminase (ω-TA). Although both enzymes have a high sequence similarity (86% identities, 92% positives), there are differences in the active center, which allow VboTA to accept a broader substrate spectrum. Both enzymes have also a different temperature stability and temperature optimum.VboTA deaminates the D-form of aromatic β-amino acids, such as β-homophenylalanine and β-phenylalanine as well as aliphatic β-amino acids, such as β-homoalanine and β-leucine. The optimal reaction conditions turned out to be 32 °C and pH 9. Kinetic resolution lead to high enantiomeric excess of 86.6% to >99.9%, depending on the amino donor/acceptor pair. In contrast to many other ω-TAs, VboTA has a broad substrate spectrum and uses both aromatic or aliphatic amino acids. With γ-amino acids as substrates, VboTA showed no activity at all.

Conformationally Restricted β-Sheet Breaker Peptides Incorporating Cyclic α-Methylisoserine Sulfamidates.

Peptides containing variations of the β-amyloid hydrophobic core and five-membered sulfamidates derived from β-amino acid α-methylisoserine have been synthesized and fully characterized in the gas phase, solid state and in aqueous solution by a combination of experimental and computational techniques. The cyclic sulfamidate group effectively locks the secondary structure at the N-terminus of such hybrid peptides imposing a conformational restriction and stabilizing non-extended structures. This conformational bias, which is maintained in the gas phase, solid state and aqueous solution, is shown to be resistant to structure templating through assays of in vitro β-amyloid aggregation, acting as β-sheet breaker peptides with moderate activity.

Photocatalytic Alkylation of C(sp3 )-H Bonds Using Sulfonylhydrazones.

The ability to construct C(sp3 )-C(sp3 ) bonds from easily accessible reagents is a crucial, yet challenging endeavor for synthetic organic chemists. Herein, we report the realization of such a cross-coupling reaction, which combines N-sulfonyl hydrazones and C(sp3 )-H donors through a diarylketone-enabled photocatalytic hydrogen atom transfer and a subsequent fragmentation of the obtained alkylated hydrazide. This mild and metal-free protocol was employed to prepare a wide array of alkyl-alkyl cross-coupled products and is tolerant of a variety of functional groups. The application of this chemistry further provides a preparatively useful route to various medicinally-relevant compounds, such as homobenzylic ethers, aryl ethyl amines, β-amino acids and other moieties which are commonly encountered in approved pharmaceuticals, agrochemicals and natural products.

Oligoarginine-Conjugated Peptide Foldamers Inhibiting Vitamin D Receptor-Mediated Transcription.

The vitamin D receptor (VDR) is a nuclear receptor, which is involved in several physiological processes, including differentiation and bone homeostasis. The VDR is a promising target for the development of drugs against cancer and bone-related diseases. To date, several VDR antagonists, which bind to the ligand binding domain of the VDR and compete with the endogenous agonist 1α,25(OH)D3, have been reported. However, these ligands contain a secosteroidal skeleton, which is chemically unstable and complicated to synthesize. A few VDR antagonists with a nonsecosteroidal skeleton have been reported. Alternative inhibitors against VDR transactivation that act via different mechanisms are desirable. Here, we developed peptide-based VDR inhibitors capable of disrupting the VDR-coactivator interaction. It was reported that helical SRC2-3 peptides strongly bound to the VDR and competed with the coactivator in vitro. Therefore, we designed and synthesized a series of SRC2-3 derivatives by the introduction of nonproteinogenic amino acids, such as β-amino acids, and by side-chain stapling to stabilize helical structures and provide resistance against digestive enzymes. In addition, conjugation with a cell-penetrating peptide increased the cell membrane permeability and was a promising strategy for intracellular VDR inhibition. The nona-arginine-conjugated peptides 24 with side-chain stapling and 25 with cyclic β-amino acids showed strong intracellular VDR inhibitory activity, resulting in suppression of the target gene expression and inhibition of the cell differentiation of HL-60 cells. Herein, the peptide design, structure-activity relationship (SAR) study, and biological evaluation of the peptides are described.

Diastereo- and Enantioselective Reductive Mannich-type Reaction of α,β-Unsaturated Carboxylic Acids to Ketimines: A Direct Entry to Unprotected β2,3,3 -Amino Acids.

Stereoselective construction of unprotected β-amino acids is a significant challenge owing to the lack of methods for the catalytic generation of highly enantioenriched carboxylic acid enolates. In this study, a novel copper-catalyzed diastereo- and enantioselective reductive Mannich-type reaction of α,β-unsaturated carboxylic acids was developed, which provides a direct and scalable synthetic method for enantioenriched β2,3,3 -amino acids with vicinal stereogenic centers. The protocol features in situ generation of transiently protected carboxylic acids by a hydrosilane and their diastereo- and enantioselective reductive coupling with ketimines. The synthetic utility of this process was demonstrated by a gram-scale reaction and the transformation of β-amino acids.

Use of (E,E)-Dienoic Acids as Switchable (E,E)- and (Z,E)-Dienyl Anion Surrogates via Ligand-Controlled Palladium Catalysis.

Carboxylic acids are not readily applied as carbon-based nucleophiles due to their intrinsic acidic group. Here, we demonstrate that free (E,E)-2,4-dienoic acids form electron-neutral and highest occupied molecular orbital-raised η2-complexes with Pd(0) and undergo Friedel-Crafts-type additions to imines with exclusive α-regioselectivity, giving formal dienylated products after decarboxylation. Unusual and switchable (E,E)- and (Z,E)-selectivity, along with excellent enantioselectivity, is achieved via ligand-controlled outer-sphere or inner-sphere reaction modes, respectively, which are well supported by comprehensive density functional theory calculation studies. An unprecedented formal reductive Mannich reaction between (E,E)-dienoic acids and imines is also developed to furnish enantioenriched β-amino acid derivatives.

Azumamides A-E: Isolation, Synthesis, Biological Activity, and Structure–Activity Relationship

Cyclic peptides are one of the important chemical groups in the HDAC inhibitor family. Following the success of romidepsin in the clinic, naturally occurring cyclic peptides with a hydrophilic moiety have been intensively studied to test their function as HDAC inhibitors. Azumamides A-E, isolated from Mycale izuensis, are one of the powerful HDAC inhibitor classes. Structurally, azumamides A-E consist of three D-α-amino acids and unnatural β-amino acids such as 3-amino-2-methyl-5-nonenedioic acid-9-amide (Amnna) and 3-amino-2-methyl-5-nonenoic-1,9-diacid (Amnda). Moreover, azumamides have a retro-arrangement peptide backbone, unlike other naturally occurring cyclopeptide HDAC inhibitors, owing to the D-configuration of all residues. This review summarizes the currently available synthetic methods of azumamides A-E focusing on the synthesis of β-amino acids and macrocyclization. In addition, we overview the structure-activity relationship of azumamides A-E based on reported analogs. Collectively, this review highlights the potentiality of azumamides A-E as an HDAC inhibitor and provides further developmental insight into naturally occurring cyclic peptides in HDAC inhibition.

Maillard reaction between oligopeptides and reducing sugar at body temperature: The putative anti-glycation agents.

Type 2 Diabetes mellitus (T2DM) is one of the most common chronic multifactorial diseases, which is associated with the increased concentration of glucose in the blood. Therefore, the utilization of blood lowering agents is clearly a promising approach which can lead to a suppression of the evaluated blood glucose, and thus curing T2DM and other complication. In this study, we evaluated the glucose lowering effect of a varieties of amino acids (alanine and histidine), dipeptides (carnosine and α-alanine-L-histidine), and tripeptide (glutathione) by reacting with glucose, fructose, and sucrose under 37°C and pH 7.4 to mimic their reaction in physiological condition. By measuring the reduction of reactants and the formation of Maillard reaction products over the course of 21 days' storage, we found that the glucose lowering effect of carnosine was better than the counterparts. The histidine residue in carnosine may contribute to its glucose lowing effect while β-amino acid β-alanine residue could facilitate the glucose lowering effect of carnosine by maintaining its chemical stability during the storage. These results may open up new avenues for the applications of bioactive peptide carnosine as a natural blood sugar lowering agent to control T2DM.

Taurine, a non-proteinous essential amino acid for human body systems: an overview

PurposeTaurine (2-aminoethane sulfonic acid; C2H7NO3S) is a nonprotein sulfur-containing β-amino acid present in nearly all mammalian tissues and the most ubiquitous free endogenous biomolecule in human cells. Taurine is commonly known as a conditionally essential amino acid because taurine is one of the few amino acids that are not incorporated in protein synthesis. The purpose of this study is to review the existing articles related to taurine and to give an account how useful is taurine to the different body systems. In this thorough overview, taurine is covered in terms of its essentiality, sources, advantages for neonates and the elderly, the effects of taurine deficiency, and the safety and toxicity of taurine supplements.Design/methodology/approachThis is a narrative review into the subject matter. Published articles were searched on different portals like PubMed, EMBASE, Scopus, Google Scholar, PubChem etc. The authors also evaluated the availability of taurine in commercially available energy drinks.FindingsThis comprehensive review, presents the potential clinical benefits and functional properties of taurine as a conditionally essential amino acid. Energy drinks containing taurine (and their concentration) are also reported in this review.Originality/valueThis is the first data that the authors are aware of that shows taurine content in a variety of energy drinks on the market.

Re-designing Escherichia coli for high-yield production of β-alanine by metabolic engineering

β-Alanine is the only natural β-amino acid and an important precursor for pantothenic acid (vitamin B5) synthesis. In this work, to improve the β-alanine fermentative production, collaborative modifications mainly focused on aspartate ammonia-lyase (aspA), phosphoenolpyruvate (PEP) – pyruvate (PYR) – oxaloacetate (OAA) – L-aspartate nodes, glucose uptake system, and β-alanine uptake system were performed, including knock out of aspA, reducing the consumption of central metabolic nodes PEP and PYR, enforcement of the non-PEP-dependent transferase system (non-PTS), inactivation of gluconeogenesis through deleting pck gene, and disruption of β-alanine uptake system. As a result, a significantly enhanced β-alanine accumulation was achieved. The β-alanine titer was increased to 6.67 g/L (final strain B15) from 2.46 g/L (original strain B1) in shake flask fermentation, and a titer of 41.12 g/L was achieved in 5-L fermentor fermentation. With the presence of succinic acid (0.25 g/L), the β-alanine titer eventually reached 52.61 g/L at 72 h, and a high productivity (0.73 g/L/h) and yield (0.268 g/g glucose) were also obtained. The yield was relatively higher compared with the reported levels and the B15 exhibited a remarkable fermentation stability over a long period. This result laid foundation for industrialization of β-alanine fermentative production.

Reversal and Preventive Pleiotropic Mechanisms Involved in the Antipsychotic-Like Effect of Taurine, an Essential β-Amino Acid in Ketamine-Induced Experimental Schizophrenia in Mice.

Schizophrenia is a life disabling, multisystem neuropsychiatric disease mostly derived from complex epigenetic-mediated neurobiological changes causing behavioural deficits. Neurochemical disorganizations, neurotrophic and neuroimmune alterations are some of the challenging neuropathologies proving unabated during psychopharmacology of schizophrenia, further bedeviled by drug-induced metabolic derangements including alteration of amino acids. In first-episode schizophrenia patients, taurine, an essential β-amino acid represses psychotic-symptoms. However, its anti-psychotic-like mechanisms remain incomplete. This study evaluated the ability of taurine to prevent or reverse ketamine-induced experimental psychosis and the underlying neurochemical, neurotrophic and neuroinmune mechanisms involved in taurine's clinical action. The study consisted of three different experiments with Swiss mice (n = 7). In the drug alone, mice received saline (10mL/kg/p.o./day), taurine (50 and 100mg/kg/p.o./day) and risperidone (0.5mg/kg/p.o./day) for 14days. In the preventive study of separate cohort, mice were concomitantly given ketamine (20mg/kg/i.p./day) from days 8 to 14. In the reversal study, mice received ketamine for 14days before taurine or risperidone treatments from days 8 to 14 respectively. Afterwards, stereotypy behaviour, social, non-spatial memory deficits, and body weights were assessed. Neurochemical (dopamine, 5-hydroxytryptamine, glutamic acid decarboxylase, (GAD)), brain derived-neurotrophic factor (BDNF) and pro-inflammatory cytokines [tumor necrosis factor-alpha, (TNF-α), interleukin-6, (IL-6)] were assayed in the striatum,prefrontal-cortex andhippocampal area. Taurine attenuates ketamine-induced schizophrenia-like behaviour without changes in body weight. Taurine reduced ketamine-induced dopamine and 5-hydroxytryptamine changes, and increased GAD and BDNF levels in the striatum, prefrontal-cortex and hippocampus, suggesting increased GABAergic and neurotrophic transmissions. Taurine decreases ketamine-induced increased in TNF-α and IL-6 concentrations in the striatum, prefrontal-cortex and hippocampus. These findings also suggest that taurine protects against schizophrenia through neurochemical modulations, neurotrophic enhancement, and inhibition of neuropathologic cytokine activities.

Taurine attenuated methotrexate-induced intestinal injury by regulating NF-κB/iNOS and Keap1/Nrf2/HO-1 signals

Methotrexate (MTX) is a well-known and widely used cytotoxic chemotherapeutic agent. However, intestinal mucosa damage is a serious adverse effect of MTX. Taurine (TUR) is a sulfur-containing free β-amino acid with antioxidant and therapeutic value against several diseases. The current study aimed to determine the protective effect of TUR against MTX-induced intestinal injury. Rats were allocated into four groups. The first group received vehicles only. The second group received TUR at a dose of 250 mg/kg i.p. For induction of intestinal injury, the rats in the third group were given MTX once at a dose of 20 mg/kg, i.p. The fourth group received TUR 7 days before and 7 days after MTX, as previously described. TUR significantly attenuated the cytokine release by suppressing NF-κB and iNOS expressions. Moreover, cotreatment with TUR attenuated the increased MDA level while it enhanced the antioxidant GSH and SOD levels mediated by effective downregulation of Keap1 expression, while the expression of Nrf2, HO-1, and cytoglobin were up-regulated. Additionally, TUR mitigated the apoptosis and proliferation indices by decreasing the elevated levels of intestinal PCNA and caspase-3. Finally, TUR potently increased the cytotoxic activity of MTX toward Caco-2, MCF-7, and A549 cancer cells. In conclusion, TUR was a promising agent for relieving MTX-mediated intestinal injury via various antioxidant, anti-inflammatory, and antiapoptotic mechanisms.

Both Amide-Bearing α- and β-Amino Acids from Natural Aspartic Acid Are Efficient Organocatalysts for Enantioselective Aldol Reactions

AbstractThis work aims to compare and explore the different catalytic efficiencies of structurally similar α- and β-amino acids in an asymmetric aldol transformation. Interestingly, aspartic acid is not only an α-amino acid, but also a β-amino acid. Thus, by modifying one of the two acidic groups of aspartic acid, two sets of α- and β-amino acids, 14 amino acids in total, were prepared and used as organocatalysts. The two types of amino acid, interestingly, achieved similar high catalytic efficiencies in the asymmetric aldol transformation under different optimal conditions. The ideal β-amino acid, in some cases, even achieved significantly higher enantioselectivity than the ideal α-amino acid, although α-amino acids are extensively demonstrated to be highly efficient organocatalysts in this asymmetric transformation.